The importance of genotypic differences in the susceptibility to alcoholism in man, and their influence on ethanol sensitivity, tolerance, and withdrawal severity in animals, is achieving ever greater recognition. While we know that susceptibility to almost all aspects of alcohol's effects in animals is to some degree inherited, we have little idea yet what specifically is inherited. The proposed research will provide an animal genetic model for an unique biochemical and behavioral response to ethanol that will allow us to unravel some of the genetic relationships among different aspects of ethanol responsiveness. The proposed project will develop lines of mice that differ genetically in their sensitivity to ethanol's effect to stimulate activity in an open field. Using within-family selective breeding, two Activity Prone (ACP) and two Activity Resistant (ACR) lines will be developed. The existence of replicate lines will allow clear differentiation of correlated responses to selection from those arise between the given pair of ACP and ACR lines by chance. Methods will be adopted to insure that the lines differ in activity sensitivity to the same brain level of ethanol. The major long-term goal of the proposed selective breeding study is to shed light on an ubiquitous, easily assessed response to ethanol (activity) that potentially mimics biochemical and behavioral indices of the euphoriant response in man. Previous research has identified ethanol-induced activity as a key response that is: (1) easily measured; (2) has clear dose-effect and temporal characteristics; (3) is genetically mediated; (4) may serve as a biochemical and behavioral model for ethanol's behavioral stimulant and euphoriant effects in man; and (5) does not appear to display tolerance development. The successful selection of the proposed lines will provide a unique genetic model for the behaviorally-stimulating effects of ethanol.